To assess the effect of two withdrawal strategies over two years in patients with stable remission for more than 8 months on combination therapy with infliximab and antimetabolites, and demonstrate that continued combination of infliximab and…
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
There will be two co-primary efficacy end points
Relapse rate at 2 years, relapse being defined by either one of the following
events:
- A CDAI*250 at any visit or between 150 and 250 with an increase of at least
70 points, over two consecutive visits one week apart. This must be associated
with a CRP > 5 mg/l or a fecal calprotectin > 250 microg/g
- A new opening fistula, perianal or entero-cutaneous
- An intra-abdominal abscess (size of at least 3 cm) or perianal abscess (size
of at least 2 cm) (also considered as treatment failure, see below)
- An episode of intestinal obstruction due to Crohn*s lesions confirmed by
medical imaging and requiring hospitalisation (also considered as treatment
failure, see below)
Mean restricted time spent in remission
This time will be computed in all patients, from baseline (CDAI <150 and with
absence of fistula drainage) until relapse, as defined above, within the 2
first years. First and subsequent remissions (under the predefined treatment
strategy according to randomization) will be summed up within the first two
years.
Secondary outcome
- Time to relapse in each arm.
- Factors associated with time to relapse.
- Time to relapse according to CRP and calprotectin value measured every 2
months over the follow up.
- Sustained clinical remission defined by CDAI<150 without steroids over two
years.
- Treatment failure rate. Treatment failure is defined by not achieving
remission after treatment adaptation following a relapse according to protocol
(CDAI<150 or, in case of relapse defined by the occurrence of a new fistula,
the absence of fistula closure, defined clinically by the persistence of an
opened fistulous track and/or drainage upon gentle pressure). Treatment failure
will also be defined by a major treatment side-effect leading to treatment
cessation. The occurrence of an intra-abdominal or perianal abscess and the
occurrence of an intestinal obstruction due to Crohn*s lesions and requiring a
surgical resection or an endoscopic dilatation are also directly considered as
treatment failure and will not be managed by treatment adaptation according to
protocol.
- Time to treatment failure.
- Incidence and severity of acute or delayed infliximab infusion reaction.
Severity of the acute infusion reaction wil be assessed according to Ring et
Messmer classification (6).
- Tissue damage progression will be assessed by the Lémann Index absolute and
relative change between baseline and end of the study (2 years).
- Other secondary judgement criteria: CDEIS/SES-CD, MaRIA score, CDMRIS,
disability index, adverse events and SAE, events related to re-infusions,
trough levels of infliximab, ATI, hsCRP, fecal calprotectin, direct medical
costs, work productivity and activity index, short health scale, EQ-5D.
Background summary
The SONIC trial has demonstrated that infliximab+azathioprine combo therapy was
superior to infliximab monotherapy and azathioprine monotherapy to achieve
steroid free remission and mucosal healing in anti-metabolites-naïve
steroid-dependent or steroid-refractory patients. Despite this superiority,
maintaining such combo therapy long term may generate cost and safety issues. A
survey in several European and North-American centres suggests that a minority
of patients are currently treated long term with combo-therapy.
The STORI trial suggests that a steroid free remission may be maintained, after
infliximab discontinuation, in half of the patients having reached sustained
steroid-free remission with infliximab+antimetabolites combo-therapy. It also
suggests that infliximab retreatment is safe and effective in relapsing
patients.
The STEP-UP TOP-DOWN trial also suggests that on demand infliximab under the
cover of an anti-metabolites maintenance is feasible.
The IMID trial suggests that azathioprine discontinuation after at least 6
months of combination therapy may have limited or no impact on disease activity.
A prospective randomized multi-arm study is necessary to assess the benefits of
the continuation of a combination therapy and the feasibility of infliximab or
antimetabolites discontinuation in patients in sustained steroid free remission
after prolonged treatment with a combination of infliximab and
anti-metabolites.
Study objective
To assess the effect of two withdrawal strategies over two years in patients
with stable remission for more than 8 months on combination therapy with
infliximab and antimetabolites, and demonstrate that continued combination of
infliximab and antimetabolites or continued monotherapy with infliximab are
both superior to antimetabolites alone for maintaining sustained steroid-free
clinical remission, while antimetabolites alone are not inferior with regards
to the mean time spent in remission.
Study design
An open label, multicenter, trial with 3 parallel randomized arms will be
performed, comparing three strategies of maintenance therapy in patients in
sustained clinical remission without steroids for at least 6 months and having
been treated by a combination of anti-metabolites and infliximab for at least 8
months.
Intervention
Standard of Care medication.
First treatment arm: continuing scheduled infliximab treatment and
anti-metabolite at the same dosage.
Second arm: discontinuing infliximab and continuing the anti-metabolite at the
same dosage.
Third arm: discontinuing anti-metabolites.
Study burden and risks
Patients participating in the study are followed regularly (standard of care).
The extra load consists of taking extra tubes of blood and collecting fecal
samples and completing health questionnaires. Patients must also complete a
diary.
Hôpital Lariboisière Rue Ambroise Paré 2
Paris 75475
FR
Hôpital Lariboisière Rue Ambroise Paré 2
Paris 75475
FR
Listed location countries
Age
Inclusion criteria
* Diagnosis of Crohn's disease.
* Male or female, age > 18 years.
* Currently treated with a combination therapy with infliximab and anti-metabolites for luminal Crohn's disease.
* Combined therapy with scheduled infliximab and anti-metabolites for at least 8 months.
* Scheduled administration of infliximab 5 mg/Kg every 8 weeks over the last 4 months.
* Antimetabolites administered at a stable dosage for the last 3 months: at least 1 mg/Kg or 2 mg/Kg for mercaptopurine and azathioprine, respectively, or the highest tolerated dosage if intolerance to standard dose (lower dose than standard dose is also allowed if 6 TGN
> 235 pmol) ; at least 15 mg/week subcutaneously for methotrexate.
* Patients in steroid free clinical remission for at least 6 months according to retrospective assessment of the patients' files.
* CDAI < 150 at baseline.
* A contraceptive during the whole study for childbearing potential female patients.
* Patients able to understand the information provided to them and to give written informed consent for the study
Exclusion criteria
* Patients who have presented a severe acute or delayed reaction to infliximab.
* Perianal fistulae as the main indication for infliximab treatment
* Active perianal/abdominal fistulae at time of inclusion, defined by active drainage
* Patients with ostomy or ileoanal pouch
* Pregnancy or planned pregnancy during the study
* Inability to follow study procedures as judged by the investigator
* Non-compliant subjects.
* Participation in another therapeutic study
* Steroid use *6 months prior to screening
* Currently receiving steroids, immunosuppressive agents (other than purine, methotrexate), biologic treatment (other than infliximab) or thalidomide
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-002311-41-NL |
| ClinicalTrials.gov | NCT02177071 |
| CCMO | NL63506.018.17 |